Metalloproteins play an important role in many physiological and pathophysiological processes. The metalloproteins are accordingly divided into various groups corresponding to their substrate. Many metalloproteins hydrolyze proteins (metalloproteases), while others cleave ester groups (e.g. phosphodiesterases). Examples of metalloproteases are Angiotensin Converting Enzyme (ACE) and the neutral endopeptidases (NEP, EC 3.4.24.11), which participate in the metabolism of a series of blood pressure-regulating peptides (e.g. angiotensin I and ANF (atrial natriuretic factor)). ACE catalyzes the cleavage of angiotensin I to the blood pressure-lowering angiotensin II. NEP is responsible for the degradation of the vasodilating peptide ANF. Endothelin Converting Enzyme (ECE) cleaves the endogenous, inactive big-endothelin to the effective vasoconstrictor endothelin-1, a peptide consisting of 21 amino acids. The inhibition of these enzymes has a great therapeutic significance for the treatment of high blood pressure, cardiac insufficiency, kidney failure and apoplexy. BMP-1 (bone morphogenic factor 1) has been recognized as a metalloprotease which plays a role in the conversion of procollagen into fibrillary collagen. Inhibitors of this enzyme are suitable for the treatment of fibroses and sclerotic processes and can also favourably influence scar formation in the healing of wounds (Proc. Natl. Acad. Sci. USA 1996, 93, 5127, Science 1996, 271, 360).
While ACE inhibitors are already used therapeutically (e.g. captopril, enalapril, Exp. Opin. Ther. Pat. 1996, 6,1147), no clinically useful active substances which are free from undersirable side effects and which are orally available are known for the metalloproteases such as NEP and ECE (literature references: NEP: Pharmacol. Rev. 1993, 45, 87; ECE: Bioorg. Med. Chem. Lett. 1996, 6, 2317, literature re phosphoramido type inhibitors). Hitherto, no low molecular inhibitors for BMP-1 are known.
The matrix metalloproteases (MMPs) represent one group of metalloproteases. Various groups of metalloproteases are known. One such group is as known as the matrix metalloproteases (MMPs). In normal tissue an equilibrium exists between the synthesis and degradation of the extracellular matrix. The extracellular matrix is synthesized by at least three groups of proteases, namely collagenases, gelatinases and stromelysins. Normally, specific inhibitors of these enzymes, such as e.g. .alpha..sub.2 -macroglobulin and TIMP (tissue inhibitor of metalloproteases), make sure that an excessive degradation of the extracellular matrix does not take place. A related group of proteases comprises the adamalysins with their most prominent member being TNF-.alpha. converting enzyme (TACE) (Moss et al., Nature 1996, 385, 733).
At least 11 different, but very homologous matrix metalloproteases have been characterized, inter alia the interstitial fibroblast collagenase (MMP-1, HFC), the neutrophilic collagenase (MMP-8, HNC), two gelatinases, stromelysins (e.g. HSL-1) and matrilysin (Birkedal-Hansen, H., Moore, W. G. I., Bodden, M. K. Windsor, L. J., Birkedahl-Hansen,B., DeCarlo, A., Engler, J. A., Crit. Rev. Oral Biol. Med. 1993, 4, 197-250). These proteinases share a series of structural and functional properties, but differ in their substrate specificity. Only HNC and HFC cleave native triple helical collagen of types I, II and III. Fragments of 3/4 and 1/4 of the original length thereby result. The melting point of the collagen is lowered by this degradation. Subsequently, it can be attacked by other matrix-degrading enzymes.
The uncontrolled excessive degradation of these matrices is typical for many pathological situations which manifest themselves, such as e.g. rheumatoid arthritis, osteoarthritis, multiple sclerosis, tumour metastasing, corneal ulcerations, inflammatory processes and various disorders of the bones and teeth.
The pathogenesis of these illnesses should be positively influenced by the administration of metalloproteinase inhibitors. Some of such compounds are to be found in the literature (a review will be found e.g. in Nigel R. A., Beeley et al., Curr. Opin. Ther. Patents 1994, 4(1), 7). These are primarily peptides having a hydroxamic acid, thiol or phosphine residue as the zinc-binding group (inter alia e.g. WO-A-9209563 of Glycomed, EP-A-497192 of Hoffmann-La Roche, WO-A-489577 of Celltech, EP-A-320118 of Beecham, U.S. Pat. No. 4,595,700 of Searle).
Phosphodiesterases (PDEs) are a group of proteins which hydrolyze the regulatory-acting cyclic nucleotides (cAMP or CGMP) in cells to the inactive mononucleotides. The distribution of the PDE isoenzymes differs in individual types of cell. Thus, the isoform is quite prominent in monocytes/macrophages, the cells which synthesize the main amount of proinflammatory Tumour Necrosis Factor .alpha. (TNF.alpha.). A zinc-binding domain in the catalytic centre has been detected for this enzyme and, moreover, its activity is dependent on divalent cations (J. Biol. Chem. 1994, 269, 22477), rolipram inhibits PDE4 and thereby brings about an inhibition of the synthesis of TNF.alpha. in vitro and in vivo (J. Med. Chem. 1998, 41, 266). The further development of rolipram has, however, been severely disrupted by massive side effects (Pharmacol. Toxicol. 1996, 78, 44). PDE-inhibitors, which have an improved compatibility based on a selective activity profile, can play a great role as inhibitors of TNF.alpha. synthesis. Moreover, PDEs can dilate the smooth musculature in the bronchi by increasing cellular cAMPs, which is utilized in the treatment of asthma therapeutically with e.g. theophylline.
Tumor necrosis factor .alpha.(TNF.alpha.) is a proinflammatory cytokine which has pathogenetic significance in a large number of illnesses. Clinically it has been shown in a multicentre, randomized double-blind study by Elliot et al. (Lancet 1994, 344, 1105-1110) that a neutralizing antibody against TNF.alpha. brings about a rapid and pronounced improvement of the disease symptoms in patients with rhumatoid arthritis. In the meanwhile, clinical data has been published by Dullemen et al. in Gastroenterology 1995, 109. 129-135 which demonstrates a therapeutic activity of such an antibody in patients with Crohn's disease. Furthermore, it has been shown in animal experiments that rolipram, which likewise blocks the synthesis of TNF.alpha., has a very good activity in animal models for multiple sclerosis. Thalidomide, a further TNF.alpha.-inhibiting substance, has been used clinically for the treatment for chronic graft versus host disorders, in the treatment of nodular leprosy and of patients with lupus erythematodes. Moreover, it has been shown that this substance supresses the proliferation of HIV.
TNF.alpha. appears to have direct pathogenic significance in the following disease conditions:
degenerative joint diseases, rheumatoid arthritis, inflammation, allergy, ARDS, asthma, cardiac infarction, chronic cardiac insuffiency, HIV infection, Crohn's disease, ulcerative colitis, psoriasis, dermatitis, actinokeratoses, vasculitides, septic shock, transplant rejection, multiple sclerosis, ulcers, diabetes, chronic graft versus host disorders, leprosy and other infectious diseases, lupus erythematodes, paradontoses and in the case of other illnesses. PA1 R.sub.2 PA1 R.sub.4 PA1 R.sub.5 and R.sub.6 PA1 R.sub.7 PA1 X PA1 R.sub.8 PA1 R.sub.9 and R.sub.10 PA1 R.sub.11 and R.sub.12 PA1 R.sub.13 and R.sub.14 PA1 as well as their tautomers, enantiomers, diastereomers, racemates and physiologically compatible salts or esters and substances which are hydrolyzed or metabolised in vivo to compounds of formula I. PA1 R.sub.2 PA1 R.sub.4 PA1 R.sub.5 and R.sub.6 PA1 R.sub.7 PA1 X PA1 R.sub.8 PA1 R.sub.9 and R.sub.10 PA1 R.sub.11 and R.sub.12 PA1 R.sub.13 and R.sub.14 PA1 a) reacting a compound of formula I in which R.sub.1, R.sub.2, R.sub.3, R.sub.5 and R.sub.6 have the given significance and R.sub.4 signifies HON(R.sub.7)COCH.sub.2 --, wherein R.sub.7 has the given significance, or an alkali metal or alkaline earth metal salt thereof, with a compound yielding the group R.sub.8 --X--, wherein X and R.sub.8 have the given significance, or PA1 b) reacting a compound of formula I in which R.sub.4 signifies carboxymethyl or a reactive group derived therefrom with a compound R.sub.8 XON(R.sub.7)H, wherein X, R.sub.7 and R.sub.8 have the significance given above, PA1 R.sub.200 PA1 R.sub.500 and R.sub.600 PA1 R.sub.7 PA1 X PA1 R.sub.800 PA1 R.sub.900 and R.sub.1000 PA1 R.sub.13 and R.sub.14 PA1 as well as their tautomers, enantiomers, diastereomers, racemates and physiologically compatible salts or esters and substances which are hydrolyzed or metabolised in vivo to compounds of formula la. PA1 R.sub.401 PA1 R.sub.7 PA1 X PA1 R.sub.801 PA1 NR.sub.901 and R.sub.1001 PA1 R.sub.13 and R.sub.14 PA1 as well as their tautomers, enantiomers, diastereomers, racemates and physiologically compatible salts or esters and substances which are hydrolyzed or metabolised in vivo to compounds of formula Ib. PA1 R.sub.70 PA1 X.sub.1 signifies carbonylmethylene, ethylene or a valency bond, PA1 R.sub.802 PA1 R.sub.902 and R.sub.1002
The clinical use of monoclonal anti-TNF.alpha. antibodies can only by effected parenterally. The medicament is expensive to manufacture and requires a complex distribution logistic (refrigeration network, storage, expiry date etc.). Moreover, in 50% of patients who have received between 2 and 4 injections, the appearance of neutralizing HACAs (human anti-chimeric antibodies) has been established. This means that the trouble-free phases become shorter and shorter. The development of rolipram as an anti-TNF.alpha. therapy principle is impaired by its emetic activity. The teratogenic side effects of thalidomide and the weak TNF.alpha. blockade can likewise appear to be difficulties in a clinical development of this substance.